Potassium (K+) channels are membrane-spanning proteins that generally act to hyperpolarize neurons. Physiological studies indicate that potassium currents are found in most cells and are associated with a wide range of functions, including the regulation of the electrical properties of excitable cells. Depending on the type of potassium channel, its functional activity can be controlled by transmembrane voltage, different ligands, protein phosphorylation, or other second messengers.
Potassium channels are considered to be the most diverse class of ion channels and have several critical roles in cell function. This has been demonstrated in neurons where K+ channels are responsible, in part, for determining cell excitability by contributing to membrane repolarization following depolarization, resting membrane potential, and regulation of neurotransmitter release. The M-current has long been described, by electrophysiology recording methods and by pharmacology, as a dominant conductance in controlling neuronal excitability. The M-current is modulated by numerous neurotransmitters (acetylcholine, substance P, LHRH, and somatostatin), which can lead to either suppression or enhancement of current.
Two major physiological roles of the M-current are to set resting membrane potential and to control spike frequency adaptation. Pharmacological activation or suppression of M-currents by small molecules could have profound effects in controlling neuronal excitability. Recently, Wang et al. (1998, Science, 282:1890-1893) reported that co-assembly of the KCNQ2 and KCNQ3 potassium channels underlies a native M-current in neurons.
It is known that mutations in the KCNQ2 and KCNQ3 potassium channels are linked to benign familial neonatal convulsions (BFNC), an autosomal dominant epilepsy of newborns (Charlier et al., 1998, Nature Genetics, 18:53-55; Biervert et al., 1998, Science, 279:403-406; and Singh et al., 1998, Nature Genetics, 18:25-29). These two channels are members of the same molecular family as is the KCNQ1 potassium channel that is responsible for long-QT syndrome in the heart. Although their exact physiological functions are not well understood, the KCNQ2 and/or KCNQ3, as well as the KCNQ4 and KCNQ5, potassium channels, which are localized within the nervous system, may act to repolarize neuronal membranes that have been depolarized by Na+ and Ca++ voltage-gated ion channels. If mutations affect the KCNQ role in repolarizing the cell membrane by removing or partially reducing the outward potassium currents, it is possible that the Na+ and Ca++ ion channels would remain open longer, thus creating hyperexcitation.
An estimated 23 to 25 million Americans—about 18% of women and 6% of men—suffer from migraine pain and migraine-related symptoms (W. F. Stewart et al., 1992, JAMA, 267:64-69). Attacks are common, with more than 50% of sufferers experiencing one or more episodes per month (Rasmussen, B. K. and Breslau N., Migraine: Epidemiology. In: The Headaches, Eds. Olesen J, Tfelt-Hansen P, Welch K M A, New York, N.Y.: Raven Press; 1993:Chptr. 22:169-173).
Migraine, a heterogeneous disorder, produces a wide spectrum of pain and associated disabilities, both within and among individual sufferers. The pain spectrum includes mild pain and no disability in approximately 5-15% of migraine attacks, moderate to severe pain and disability in approximately 60-70% of attacks, and incapacitating pain and total disability in the remaining approximately 25-35% of attacks (W. F. Stewart et al., 1994, Neurology, 44(suppl4):S24-S39; R. B. Lipton and W. F. Stewart, 1993, Neurology, 43(suppl3):S6-S10).
Population-based epidemiological studies in the United States and elsewhere, have found that most people with migraine are not currently consulting a physician for their migraine attacks, and only about one-third have ever been diagnosed by a doctor (J. Edmeads et al., 1993, Can. J. Neurol Sci., 20:131-137; R. B. Lipton and W. F. Stewart, 1994, Neurology [abstract], 44(suppl2): 199; B. K. Rasmussen et al., 1992, J Epidemiol Community Health, 46:443-446; and G. Micieli, 1993, Suffering in Silence. In: Migraine: a brighter future. Ed. Edmeads J., Worthing: Cambridge Medical Publications, pp.1-7). The overwhelming majority (95% of men and 97% of women) of migraineurs, i.e., individuals who suffer from migraines, used medication to relieve pain, although only about 28% of the men and 40% of the women have used prescription medications (R. B. Lipton et al., 1992, Arch Int Med., 152:1273-1278 and D. D. Celentano et al., 1992, Headache, 32:223-228).
Although the symptom pattern varies among migraine sufferers, the severity of migraine pain justifies a need for vigorous, yet safe and effective, treatments and therapies for the great majority of cases. Needed in the art are agents that can be used to combat and relieve migraine (and diseases similar to and mechanistically related to migraine, e.g., cluster headache), and even prevent the recurrence of migraine. Also needed are anti-migraine agents which are effective in the treatment of acute migraine, and provide the potential for prophylactic treatment of migraine as demonstrated by efficacy in a model of cortical spreading depression. Thus, a clear goal in the art is to discover new, safe, nontoxic and effective anti-migraine compounds for use as drugs, and in anti-migraine compositions thereof, and treatments using the compounds and/or compositions.
In general, the migraine condition, with or without aura, has a variety of characteristic features. Migraine attacks are episodic and self-limited. The duration of untreated or unsuccessfully-treated migraine attacks can be from several hours to several days (e.g., about four hours to about three days). Migraine attacks are relatively infrequent, with about seventy-five percent of migraine sufferers experiencing less than or equal to three attacks per month (W. F. Stewart et al., 1992, JAMA, 267:64-69; W. F. Stewart et al., 1994, Neurology, 44(suppl4):S24-S39; and R. B. Lipton and W. F. Stewart, 1993, Neurology, 43(suppl3):S6-S10). Common pain characteristics of migraines include pain in a unilateral location, with a pulsating quality. Pain is usually of moderate to severe intensity and is aggravated by routine physical activity. One or more of a cluster of symptoms is recognized to frequently accompany migraines, namely, nausea and/or vomiting, photophobia, phonophobia, and functional disability, i.e., difficulty in performing routine work-related and non-work-related tasks.
The prodrome phase of migraine, or the aura phase (when it occurs), are symptoms which are known to precede an acute migraine attack and severe migraine pain. Treatments are also needed to provide not only relief from a full-blown migraine attack, but also, symptomatic relief by reducing or alleviating the development of full-blown migraine attack. As will be appreciated by the routine practitioner, the prodrome phase of a condition of migraine typically occurs before aura and before severe or throbbing migraine pain. Frequently during prodrome, the migraine sufferer experiences mood changes, lethargy and tiredness.
It will also be appreciated that migrainous aura, which is frequently experienced by about 20% of migraine sufferers, precedes severe migraine pain and throbbing. Aura involves distinctive auditory and visual distortions, which may involve visual scotomas, or even hemianopia and speech abnormalities, that develop prior to severe migraine pain and throbbing.
In view of the serious and debilitating effects that migraine headaches impose on the sufferer, novel drugs and antimigranous agents that are capable of preventing a migraine attack before the migraine sufferer experiences intense, severe migraine pain and related discomforts would be especially advantageous in the art. In addition, new drugs and compounds that are capable of providing relief from an actual migraine attack after the prodrome and/or aura phases, and once migraine pain has developed, would clearly benefit the large number of individuals who suffer from migraine. It would be especially advantageous if new drugs and compounds were developed which could reduce, ameliorate, eliminate or prevent one, or a number of, the characteristic cluster of symptoms, namely, nausea, photophobia, phonophobia and basic functional disabilities, that are further associated with migraine and migraine pain that occur after the prodrome phase of a migraine headache. It would be a further benefit and advantage to have a remedy for the amelioration, relief, and/or removal of cluster headache discomfort and pain, for example in the form of novel agents and compounds that to treat and/or prevent the cluster headache problem.
Because migraine afflicts a large percentage of the population, there is a need to discover compounds and agents that are useful in therapeutics and treatments, and as components of pharmaceutical compositions, for reducing, ameliorating, or alleviating the pain and discomfort of migraine headache and other symptoms of migraine. There is also a need for preventative treatments to ward off migraine attacks. The present invention satisfies such needs by providing compounds that function as openers of the KCNQ family of potassium channel proteins to serve as anti-migraine agents or drugs and to comprise compositions for the treatment of migraine, as described herein.
U.S. Pat. No. 5,869,509 to J. L. Romine et al. (“the '509 patent”) discloses diphenyl heterocyclic oxadiazolone derivatives and U.S. Pat. No. 6,034,113 to P. Hewawasam et al. (“the '113 patent”), discloses derivatives of 1,3,4-oxadiazolone, both of which are disclosed to be useful in the treatment of disorders that are responsive to the opening of the large conductance calcium-activated potassium channels, also called maxi-K channels. Because of their voltage and calcium dependence, maxi-K channels are distinct from KCNQ potassium channels, which are only voltage dependent. In addition, the pharmacology and kinetics of maxi-K channels versus KCNQ channels are frequently quite different, and the large conductance or maxi-K channels are responsive to the opener compounds specifically disclosed in the '509 and '113 patents. Thus, the compounds and their uses described in these patents are distinct from those of the present invention.
U.S. Pat. No. 6,117,900 to C. Rundfeldt et al. describes retigabine as an agent for use in methods of treating the symptoms of various types of neuropathologic pain. The patent does not disclose the use of novel central nervous system (CNS) KCNQ potassium channel protein opener or activator compounds to reduce hyperpolerization of neurons in the trigeminal caudal nucleus, as described herein for the amelioration or alleviation of migraine.